We recently initiated experiments to test the hypothesis that familial aortic aneurysms are caused by mutations in the type III procollagen gene. We found that the first family we used to test the hypothesis proved positive. Therefore, we propose here to test the hypothesis further and develop simple DNA tests that can be used to identify members of families predisposed to develop aortic aneurysms so that the patient can be monitored by non-invasive procedures and preventative surgery can be carried out before the aneurysms rupture. Specifically, we propose to: (1) Collect fibroblasts from 50 to 100 patients with aortic aneurysms. (2) Determine whether or not the patients had mutations in the type Ill procollagen gene. (3) If mutations are found, prove that the mutations cause changes in the biological functions of type Ill procollagen. (4) Develop simple DNA tests based on polymerase chain reaction that can be used to identify family members predisposed to the development of the aortic aneurysms. (5) Develop procedures for more rapid detection of mutations in the type Ill procollagen gene. (6) In collaborative studies with other members of our Institute, prepare transgenic mice expressing mutated type Ill procollagen genes and determine whether the transgenic mice are useful models for defining molecular etiology of the aortic aneurysms and possible therapies for the disease. (7) If no mutation in type III procollagen gene is found in a given family with aortic aneurysms, we will move on to the next candidate gene, the second major structural component of aortic wall, elastin.